Preparation of 2',3'-oxirane-fused carbocyclic nucleosides based on N-substituted 2-azabicyclo[2.2.1]-hept-5-en-3-ones

Article abstract of DOI:10.3987/COM-04-S(P)19

The epoxidation of N-substituted 2-azabicyclo[2.2.1]hept-5-en-3-ones (1) led to the exo-selective formation of epoxides (2), and the use of 2 for the preparation of 2',3'-oxirane-fused carbocyclic nucleosides (10) was attempted.

Full text of DOI:10.3987/COM-04-S(P)19

HETEROCYCLES, Vol. 64, 2004
241
HETEROCYCLES, Vol. 64, 2004, pp. 241 - 248
Received, 9th July, 2004, Accepted, 16th August, 2004, Published online, 17th August, 2004
PREPARATION
OF
2’,3’-OXIRANE-FUSED
CARBOCYCLIC
NUCLEOSIDES BASED ON N-SUBSTITUTED 2-AZABICYCLO[2.2.1]-
HEPT-5-EN-3-ONES
Minoru Ishikura,* Kota Matsumoto, and Atsushi Murakami
Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido,
Ishikari-Tobetsu, Hokkaido 061-0293, Japan. e-mail: ishikura@hoku-iryo-u.ac.jp
Abstract – The epoxidation of N-substituted 2-azabicyclo[2.2.1]hept-5-en-3-ones
(1) led to the exo-selective formation of epoxides (2), and the use of 2 for the
preparation of 2’,3’-oxirane-fused carbocyclic nucleosides (10) was attempted.
2-Azabicyclo[2.2.1]hept-5-en-3-one (ABH) (1a) is a class of bicyclic lactam with greater strain energy,
and we devoted attention to the development of its synthetic potential.1 We have previously reported that
cycloaddition of diazomethane2 and azides3 to N-substituted ABH (1) stereoselectively led to
cyclopropane- and aziridine-fused ABHs, which were valuable for the preparation of 2’,3’-methano- and
2’,3’-epimino-carbocyclic nucleoside derivatives. In due course, we have also become interested in the
preparation of 2’,3’-oxirane-fused carbocyclic nucleosides,4 for which the conversion of epoxide (2),
available by the epoxidation of 1, should serve as a concise approach. There are only a few reports5 of the
epoxidation of 1a using oxone under pH-controlled conditions and m-CPBA, but the detailed descriptions
have not been given. Thus, we initially targeted the epoxidation of N-substituted ABHs (1).
O
O
[O]
O
N
N
R
R
1
2
a: R=H
a: R=H
b: R=Boc
c: R=Cbz
d: R=Bn
b: R=Boc
c: R=Cbz
d: R=Bn
e: R=TBDMS
e: R=TBDMS
Scheme 1
This paper is dedicated to Dr. Pierre Potier on the occasion of his 70th birthday.

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HETEROCYCLES, Vol. 64, 2004
We first investigated the epoxidation of 1 using m-CPBA. Attempted epoxidation of 1a using m-CPBA
(2 equiv.) in CH2Cl2 at room temperature for 48 h resulted in very poor yield of 2a, in contrast to the
availability of 2a from 1a using m-CPBA.5b The epoxidation of 1b-e with m-CPBA produced epoxides
(2b-e) as seen in Table, and a significant increase in the susceptibility to epoxidation was observed when
an electron-donating group was present at the nitrogen as 1d,e. We reasoned that the electron-rich nature
of 1d,e by the neighboring participation6 between the nitrogen and the double bond might allow for such
susceptibility. Moreover, dimethyldioxorane (DMDO)7 appeared to be highly effective for the
epoxidation of 1.
Table Epoxidation of 1
1
Conditions
Yields (%) of 2
a
m-CPBA / CH2Cl2 / 48 h
5 (70)
1a
b
DMDO / CH2Cl2 / 36 h
80
m-CPBA / CH2Cl2 / 48 h
66
80
1b
b
DMDO / CH2Cl2 / 36 h
a
H2O2 / CH3CN / 48 h
-- (77)
c
a
UHP / CH2Cl2 / 36 h
-- (40)
m-CPBA / CH2Cl2 / 48 h
62
80
1c
b
DMDO / CH2Cl2 / 36 h
m-CPBA / CH2Cl2 / 48 h
63
80
1d
b
DMDO / CH2Cl2 / 36 h
a
H2O2 / CH3CN / 48 h
4 (80)
c
a
UHP / CH2Cl2 / 36 h
37 (45)
m-CPBA / CH2Cl2 / 48 h
67
85
1e
b
DMDO / CH2Cl2 / 36 h
a
H2O2 / CH3CN / 48 h
6 (74)
c
a
UHP / CH2Cl2 / 36 h
47 (25)
a
b
c
Recovery of 1 (%)
Dimethyldioxorane
Urea-hydrogen peroxide8
The proof of the stereoselective formation of epoxides (2) was obtained by NOE experiments, where no
NOE between H-6 and H-7 was observed.

HETEROCYCLES, Vol. 64, 2004
243
H
H
7
C6-H
C5-H
C1-H
O
O
5
δ 3.67
δ 3.75
δ 3.78
δ 3.52
δ 3.54
δ 3.58 δ 3.90
δ 3.59 δ 4.59
δ 3.61 δ 4.70
δ 3.25 δ 3.75
δ 3.54 δ 3.86
2a
2b
2c
2d
2e
1
6
N
H
R
H
H
NOE correlatios of 2
Next, as a study to examine the feasibility of the epoxidation taking place from the endo-side, the
epoxidation of 3, whose hydroxyl group might play a stereodirecting role, was run (Scheme 2). No
reaction occurred when we attempted to oxidize 3b using Sharpless’ method, and 3b was recovered
unchanged. On the other hand, with the failure of the epoxidation of 3b, treatment of 3a with m-CPBA
in CH2Cl2 for 24 h produced endo-epoxide (4) in 55% yield. The structure of 4 was determined on the
basis of NOE experiments with the observation of NOE between H-6 and H-7.
δ 1.84
H
H
δ 3.62
H
O
m-CPBA
O
O
N
H
N
CH2Cl2 / 24 h
55% (n=3)
δ 3.69
OH
OH
N
O
( )3
( )n
OH
O
( )3
H
3
4
δ 3.84
NOE correlations of 4
a: n=3
b: n=2
Scheme 2
With these results in hand, we attempted to use epoxide (2c) for the construction of 2’,3’-oxirane-fused
carbocyclic nucleoside derivatives (10) according to the previously reported methods.2,3 Reduction of
2c with NaBH4 produced 5a, and subsequent acetylation of 5a with Ac2O gave 5b. According to the
conventional method,2,3 removal of the N-Cbz group in 5a, followed by its subjection to the reaction with
pyrimidine (6) resulted in complex mixtures without the formation of 7 (Scheme 3). The use of 5b,
various solvents, lower temperature, and longer reaction time did not improve the reaction, and no further
optimization was attempted. The complicated situation seems to stem from higher lability of the
epoxide in 5 under the reaction conditions.

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HETEROCYCLES, Vol. 64, 2004
Cl
H2N
HN
N
NH-Cbz
1) NaBH4
2) Ac2O
1) H2 / 10% Pd-C
RO
N
2c
HO
2)
H
Cl
N
H
O
H2N
Cl
N
H
H
7
O
5a: R=H
70%
5b: R=Ac 86%
6
Scheme 3
Alternatively, the preparation of 2’,3’-oxirane-fused carbocyclic nucleosides (10) began with the
epoxidation of 8b, derived from TBDMSCl and the known 8a,9,10 as shown in Scheme 4. Treatment of
8b with m-CPBA in CH2Cl2 afforded epoxide (9a), most likely explicable by the attack of m-CPBA on 8b
from the less hindered side. The structure of 9a was confirmed based on NOE experiments. Then,
removal of the N-TBDMS group in 9a with n-Bu4NF afforded 9b, followed by treatment of 9b with
ammonia and cyclopropylamine, leading to 10a and 10b, respectively.
Cl
N
Cl
N
NH-R
N
N
N
N
N
N
N
N
N
m-CPBA
R-NH2
MeOH
N
RO
RO
RO
CH2Cl2
H
3 days / 60%
H
H
H
O
O
8a: R=H
8b: R=TBDMS
9a: R=TBDMS
9b: R=H
10a: R=H
10b: R=
43%
50%
Scheme 4
Cl
N
N
H
OR
H
H
N
N
(R=TBDMS)
H
NOE Correlations of 9a
In summary, we have shown that the epoxidation of N-substituted ABH (1) using m-CPBA and DMDO
afforded epoxides (2) in an exo-selective manner. Although we encountered a lack of success in the

HETEROCYCLES, Vol. 64, 2004
245
direct transformation of 2 to 2’,3’-oxirane-fused carbocyclic nucleosides (10), an alternative route
involving the epoxidation of 8b yielded 10.
EXPERIMENTAL
Melting points were recorded on a Yamato MP21 and are uncorrected. MS and HRMS spectra were
recorded on a Micromass AutoSpec 3100 mass spectrometer. IR spectra were measured on a Hitachi
Model 270-30 spectrophotometer. The NMR experiments were performed with a JEOL JNM-LA300 or
JNM-ECA500 spectrometer, and chemical shifts are expressed in ppm (δ) with TMS as an internal
reference. Medium pressure liquid column chromatography (MPLC) and flash column chromatography
were performed on silica gel (Silica gel 60N, Kanto Chemical Co., Inc.). Dehydrated solvents were
purchased from Kanto Chemical Co. Inc.
Compounds (1a,11 1b,9 and 1d12) were known, and compounds (1c and 1e) were prepared by the
treatment of 1a with (tert-butyl)dimethylsilylchloride and benzyl chloridocarbonate, respectively,
according to the literature.9
Benzyl 2-Azabicyclo[2.2.1]hept-5-en-3-one-2-carboxylate (1c):
mp 46-47 °C (hexane-AcOEt). IR (CHCl3): 1700 cm-1. 1H-NMR (CHCl3) δ: 2.15 (dd, 1H, J=1.4, 5.4 Hz),
2.33 (dd, 1H, J=1.4, 6.8 Hz), 3.39 (s, 1H), 5.00 (s, 1H), 5.21 (s, 2H), 6.63-6.65 (m, 1H), 6.86-6.88 (m,
13
1H), 7.26-7.41 (m, 5H). C-NMR (CDCl3) δ: 54.1, 54.9, 62.5, 67.8, 127.9, 128.2, 128.5, 138.2, 140.0,
175.7. MS m/z: 243 (M+). Anal. Calcd for C14H13NO3: C, 69.13; H, 5.34; N, 5.76. Found: C, 69.18; H,
5.53; N, 5.78.
2-[tert-Butyl(dimethyl)silyl]-2-azabicyclo[2.2.1]hept-5-en-3-one (1e):
1
bp 121 °C/ 1 mmHg. IR (neat): 1700 cm-1. H-NMR (CDCl3) δ: 0.18 (s, 3H), 0.19 (s, 3H), 0.88 (s, 9H),
2.12 (dt, 1H, J=1.1, 7.4 Hz), 2.30 (dt, 1H, J=1.7, 8.0 Hz), 3.21 (s, 1H), 4.35 (dd, 1H, J=1.7, 3.4 Hz),
13
6.62-6.66 (m, 1H), 6.74 (dd, 1H, J=2.3, 5.7 Hz). C-NMR (CDCl3) δ: -5.6, -5.5, 19.0, 26.2, 54.0, 60.7,
63.5, 138.4, 140.7, 187.2. MS m/z: 223 (M+). Anal. Calcd for C12H21NOSi: C, 64.52; H, 9.48; N, 6.27.
Found: C, 64.35; H, 9.56; N, 6.11.
Epoxidation of 1 with m-CPBA: General procedure:
A mixture of 1 and m-CPBA (2 equiv.) in CH2Cl2 was stirred at rt for the time shown in Table. Then the
mixture was diluted with AcOEt, washed with aqueous NaHCO3 and brine, and dried over anhydrous
MgSO4. The solvent was removed, and the residue was separated by MPLC with hexane-AcOEt as an
eluent to give 2.
Epoxidation of 1 with DMDO: General procedure:
A mixture of 1 and an excess amount of DMDO7 in acetone was stirred at rt for 36 h. Then the mixture
was dilute with AcOEt, washed with brine, and dried over anhydrous MgSO4. The solvent was removed,
and the residue was separated by MPLC with hexane-AcOEt as an eluent to give 2.
rel-(1R,2S,4R,5S)-3-Oxa-6-azatricyclo[3.2.1.02,4]octan-7-one (2a):
mp 122-124 °C (AcOEt-hexane) (lit.,5b mp 120-121 °C; lit.,5a 146 °C). IR (CHCl3): 3448, 3212, 3000,
1724 cm-1. 1H-NMR (CDCl3) δ: 1.68 (d, 1H, J=9.1 Hz), 1.85 (d, 1H, J=9.1 Hz), 2.89 (s, 1H), 3.58 (d, 1H,
J=3.4 Hz), 3.67 (d, 1H, J=3.4 Hz), 3.90 (s, 1H), 6.48 (s, 1H). 13C-NMR (CDCl3) δ: 31.2, 46.9, 51.5, 55.7,
180.7. MS m/z: 125 (M+).
rel-(1R,2S,4R,5S)-tert-Butyl 7-Oxo-3-oxa-6-azatricyclo[3.2.1.02,4]octane-6-carboxylate (2b):
1
mp 118-119 °C (hexane-AcOEt) (lit.,5b 115-116 °C). IR (CHCl3): 1786, 1710 cm-1. H-NMR (CDCl3) δ:
1.50 (s, 9H), 1.61 (d, 1H, J=10.3 Hz), 1.79 (d, 1H, J=10.3 Hz), 3.04 (s, 1H), 3.59 (d, 1H, J=2.8 Hz), 3.75
(d, 1H, J=2.8 Hz), 4.59 (s, 1H). 13C-NMR (CDCl3) δ: 27.1, 28.1, 48.4, 50.0, 53.2, 59.0, 83.4, 149.8,
173.5. MS m/z: 225 (M+).
rel-(1R,2S,4R,5S)-Benzyl 7-Oxo-3-oxa-6-azatricyclo[3.2.1.02,4]octane-6-carboxylate (2c):

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HETEROCYCLES, Vol. 64, 2004
mp 105-106 °C (hexane-AcOEt). IR (CHCl3): 1794, 1768, 1718 cm-1. 1H-NMR (CDCl3) δ: 1.65 (d, 1H,
J=10.2 Hz), 1.84 (dd, 1H, J=1.5, 10.2 Hz), 3.09 (t, 1H, J=1.5 Hz), 3.61 (dd, 1H, J=1.5, 3.4 Hz), 3.78 (dd,
1H, J=1.5, 3.4 Hz), 4.70 (t, 1H, J=1.5 Hz), 5.26 (s, 2H), 7.31-7.44 (m, 5H). 13C-NMR (CDCl3) δ: 27.1,
48.1, 49.7, 52.9, 59.1, 68.3, 128.2, 128.5, 128.7, 135.1, 151.1, 172.9. MS m/z: 259 (M+). Anal. Calcd for
C14H13NO4: C, 64.86; H, 5.05; N, 5.40. Found: C, 65.11; H, 5.12; N, 5.30.
rel-(1R,2S,4R,5S)-6-Benzyl-3-oxa-6-azatricyclo[3.2.1.02,4]octan-7-one (2d):
1
Oil. IR (neat): 1704 cm-1. H-NMR (CDCl3) δ: 1.57 (d, 1H, J=9.7 Hz), 1.77 (d, 1H, J=9.7 Hz), 2.98 (s,
1H), 3.25 (d, 1H, J=2.8 Hz), 3.52 (d, 1H, J=2.8 Hz), 3.75 (s, 1H), 4.32 (d, 1H, J=14.9 Hz), 4.42 (d, 1H,
J=14.9 Hz), 7.72-7.33 (m, 5H). 13C-NMR (CDCl3) δ: 30.3, 46.1, 47.3, 51.8, 55.4, 59.7, 128.0, 128.3,
128.4, 128.9, 129.0, 137.4, 177.1. HRMS m/z: Calcd for C13H13NO2: 215.0946. Found: 215.0939.
rel-(1R,2S,4R,5S)-6-[tert-Butyl(dimethyl)silyl]-3-oxa-6-azatricyclo[3.2.1.02,4]octan-7-one (2e):
Oil. IR (neat): 1710, 1696 cm-1. 1H-NMR (CDCl3) δ: 0.19 (s, 3H), 0.28 (s, 3H), 0.90 (s, 9H), 1.56 (d, 1H,
J=9.8 Hz), 1.78 (d, 1H, J=9.8 Hz), 2.87 (s, 1H), 3.54 (br s, 2H), 3.86 (s, 1H). 13C-NMR (CDCl3) δ: -5.2,
-4.8, 18.8, 26.3, 51.5, 48.3, 51.0, 55.1, 59.4, 183.4. HRMS m/z: Calcd for C12H21NO2Si: 239.1341.
Found: 239.1328.
rel-(1R,4R)-2-(3-Hydroxypropyl)-2-azabicyclo[2.2.1]hept-5-en-3-one (3a):
After a mixture of 1a (1.09 g, 10 mmol) and 60% NaH (400 mg, 15 mmol) was stirred in THF (50 mL)
under ice-cooling for 30 min, 2-(3-bromopropoxy)tetrahydro-2H-pyran (3.3 g, 15 mmol) was added to the
mixture, and, then, the whole was stirred at rt overnight. Excess NaH was decomposed by the addition
of 20% NH4Cl to the mixture under ice-cooling, and the mixture was extracted with AcOEt (200 mL).
The extract was washed with brine, and dried over anhydrous MgSO4. The solvent was removed, and
MeOH (30 mL) and a catalytic amount of TsOH were added to the residue. The whole was stirred at rt
for 1 h, and the mixture was extracted with ether. The extract was washed with brine and dried over
anhydrous MgSO4. The solvent was removed, and the residue was separated by MPLC with
hexane-AcOEt (5:1) as an eluent to give 1.8 g of 3a (70%).
Oil. IR (CHCl3): 3450, 1684 cm-1. 1H-NMR (CDCl3) δ: 1.50-1.65 (m, 2H), 2.15 (d, 1H, J=8.0 Hz), 2.32
(d, 1H, J=8.0 Hz), 3.15-3.30 (m, 3H), 3.34 (s, 1H), 3.35-3.45 (m, 1H), 3.46-3.55 (m, 1H), 4.17 (s, 1H),
6.67 (dd, 1H, J=1.7, 5.2 Hz), 6.84 (dd, 1H, J=1.8, 5.2 Hz). 13C-NMR (CDCl3) δ: 30.5, 39.9, 53.8, 58.9,
59.9, 64.4, 138.6, 139.9, 182.1. HRMS m/z: Calcd for C9H13NO2 167.0946. Found: 167.0953.
rel-(1R,2R,4S,5S)-6-(3-Hydroxypropyl)-3-oxa-6-azatricyclo[3.2.1.02,4]octan-7-one (4):
A mixture of 3a (167 mg, 1 mmol) and m-CPBA (344 mg, 2 mmol) was stirred at rt for 24 h. The
mixture was then diluted with AcOEt, washed with aqueous NaHCO3 and brine, and dried over
anhydrous MgSO4. The solvent was removed, and the residue was separated by MPLC with
hexane-AcOEt (5:1) as an eluent to give 100 mg (55%) of 4.
Oil. IR (CHCl3): 3428, 1692 cm-1. 1H-NMR (CDCl3) δ: 1.58-1.71 (m, 3H), 1.84 (d, 1H, J=9.7 Hz), 2.97
(s, 1H), 3.12 (br s, 1H), 3.36 (t, 2H, J=6.3 Hz), 3.55 (d, 2H, J=5.1 Hz), 3.62 (d, 1H, J=3.4 Hz), 3.69 (d,
13
1H, J=3.4 Hz), 3.84 (s, 1H). C-NMR (CDCl3) δ: 31.0, 31.9, 38.8, 47.4, 51.9, 55.5, 58.7, 61.0, 178.8.
HRMS m/z: Calcd for C9H13NO3: 183.0895. Found: 183.0897.
Benzyl rel-[(1R,2S,4S,5S)-4-Hydroxymethyl-6-oxabicyclo[3.1.0]hex-2-yl]carbamate (5a):
Reduction of 2c (155 mg, 0.6 mmol) with NaBH4 (45 mg, 12 mmol) in MeOH (30 mL) was carried out
according to the literature2,3 to give 110 mg (70%) of 5a.
1
mp 69-70 °C (AcOEt-hexane). IR (CHCl3): 3624, 3444, 1706 cm-1. H-NMR (CDCl3) δ: 1.43 (dt, 1H,
J=13.7, 4.0 Hz), 1.54 (br s, 1H), 2.49 (dt, 1H, J=13.7, 8.6 Hz), 2.83 (br s, 1H), 3.56 (dd, 1H, J=4.6, 10.3
Hz), 3.65 (dd, 1H, J=4.0, 10.3 Hz), 4.75 (br s, 1H), 5.07 (s, 2H), 5.14 (br s, 1H), 5.72-5.78 (m, 1H), 5.81
(br s, 1H), 7.25-7.36 (m, 5H). 13C-NMR (CDCl3) δ: 32.9, 40.2, 50.3, 59.3, 59.7, 63.1, 66.7, 128.1, 128.5,
136.6, 156.6. MS m/z: 263 (M+). Anal. Calcd for C14H17NO4: C, 63.87; H, 6.51; N, 5.32. Found: C,
63.67; H, 6.67; N, 5.22.

HETEROCYCLES, Vol. 64, 2004
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[rel-(1R,2R,4R,5S)-4-Benzyloxycarbonylamino-6-oxabicyclo[3.1.0]hex-2-yl]methyl Acetate (5b):
A mixture of 5a (263 mg, 1 mmol), Ac2O (153 mg, 1.5 mmol) and Et3N (202 mg, 2 mmol) in CH2Cl2 (50
mL) was stirred at rt overnight. The mixture was diluted with AcOEt, washed with brine, and dried over
anhydrous MgSO4. The solvent was removed, and the residue was separated by MPLC with
AcOEt-hexane (10:1) as an eluent to give 262 mg (86%) of 5b.
1
mp 68 °C (hexane-AcOEt). IR (CHCl3): 3420, 1720 cm-1. H-NMR (CDCl3) δ: 1.38 (d, 1H, J=14.9 Hz),
2.11 (s, 3H), 2.10-2.20 (m, 1H), 2.55-2.61 (m, 1H), 3.41 (s, 1H), 3.51 (s, 1H), 3.94 (dd, 1H, J=5.2, 11.5
Hz), 4.25-4.32 (m, 2H), 5.10 (s, 2H), 5.30 (br s, 1H), 7.32-7.35 (m, 5H). 13C-NMR (CDCl3) δ: 21.2,
32.3, 38.5, 50.8, 58.5, 65.2, 67.3, 128.1, 128.2, 129.0, 136.3, 155.6, 170.5. MS m/z: 305 (M+). Anal.
Calcd for C16H19NO5: C, 62.94; H, 6.27; N, 4.59. Found: .C, 62.96; H, 6.28; N, 4.78.
9-[rel-(1R,4S)-4-(tert-Butyldimethylsilyloxymethyl)cyclopent-2-en-1-yl]-6-chloro-9H-purine (8b):
A mixture of 8a9,10 (250 mg, 1 mmol), TBDMSCl (225 mg, 1.5 mmol), Et3N (202 mg, 2 mmol) and
DMAP (12 mg, 0.1 mmol) in CH2Cl2 (50 mL) was stirred at rt overnight. The mixture was diluted with
AcOEt, washed with brine, and dried over anhydrous MgSO4. The solvent was removed, and the
residue was separated by MPLC with AcOEt-hexane (1:2) as an eluent to give 262 mg (86%) of 8b.
mp 77°C (hexane-AcOEt). IR (CHCl3): 1595, 1565 cm-1. 1H-NMR (CDCl3) δ: 0.05 (s, 6H), 0.86 (s, 9H),
1.71 (dt, 1H, J=13.8, 6.8 Hz), 2.80 (dt, 1H, J=13.8, 8.6 Hz), 3.02-3.11 (m, 1H), 3.63 (dd, 1H, J=5.1, 9.7
Hz), 3.74 (dd, 1H, J=5.1, 9.7 Hz), 5.80-5.90 (m, 2H), 6.21 (dt, 1H, J=5.8, 2.0 Hz), 8.23 (s, 1H), 8.74 (s,
1H). 13C-NMR (CDCl3) δ: -5.2, 18.5, 26.0, 34.6, 47.9, 60.1, 65.3, 128.8, 131.9, 140.1, 143.8, 150.8,
151.5, 151.8. MS m/z: 307, 309 (M+-C4H9). Anal. Calcd for C17H25N4OClSi: C, 55.95; H, 6.90; N,
15.35. Found: .C, 55.69; H, 6.81; N, 15.43.
9-[rel-(1R,2S,4S,5S)-4-(tert-Butyldimethylsilyloxymethyl)-6-oxabicyclo[3.1.0]hex-2-yl]-6-chloro-9H-
purine (9a):
Epoxidation of 8b (364 mg, 1 mmol) with m-CPBA (344 mg, 2 mmol) was carried out for 3 days
according to the procedure described for 1, producing 228 mg (60%) of 9a.
1
mp 108-109 °C (hexane-AcOEt). IR (CHCl3): 1592, 1566 cm-1. H-NMR (pyridine-d5) δ: 0.12 (s, 3H),
0.13 (s, 3H), 0.95 (s, 9H), 1.43 (dt, 1H, J=12.1, 9.7 Hz), 2.32 (dt, 1H, J=15.5, 8.6 Hz), 3.74 (dd, 1H,
J=6.3, 9.7 Hz), 3.78-3.84 (m, 3H), 3.99 (s, 1H), 5.27 (t, 1H, J=9.2 Hz), 8.92 (s, 1H), 8.93 (s, 1H).
13C-NMR (CDCl3) δ: -5.3, 18.5, 25.9, 29.2, 42.0, 55.0, 56.9, 57.3, 62.7, 143.7, 152.0. MS m/z: 365, 367
(M+ -CH3). Anal. Calcd for C17H25N4O2ClSi: C, 53.60, H, 6.61; N, 14.71. Found: .C, 54.35; H, 6.66; N,
14.66.
[rel-(1R,2R,4R,5S)-4-(6-Chloro-9H-purin-9-yl)-6-oxabicyclo[3.1.0]hex-2-yl]methanol (9b):
A mixture of 9a (190 mg, 0.5 mmol) and n-Bu4NF (1M solution in THF, 1 mmol) in THF (50 mL) was
stirred at rt under an argon atmosphere for 30 min. The mixture was diluted with AcOEt, washed with
brine, and dried over anhydrous MgSO4. The solvent was removed, and the residue was separated by
flash chromatography with hexane-AcOEt (1:1) as an eluent to give 120 mg (90%) of 9b.
mp 174-175 °C (hexane-AcOEt). IR (nujol): 3632 cm-1. 1H-NMR (MeOH-d4) δ: 1.35 (dt, 1H, J=12.6, 9.7
Hz), 2.36 (dt, 1H, J=12.6, 8.0 Hz), 2.49 (dt, 1H, J=15.4, 8.0 Hz), 3.69 (dd, 1H, J=6.3, 10.9 Hz), 3.74 (dd,
1H, J=8.0, 10.9 Hz), 3.78 (dd, 1H, J=1.1, 2.9 Hz), 3.94 (dd, 1H, J=1.1, 2.9 Hz), 5.10 (t, 1H, J=9.0 Hz),
8.66 (s, 1H), 8.74 (s, 1H). 13C-NMR (MeOH-d4) δ: 28.4, 41.6, 55.7, 56.8, 56.9, 61.4, 130.9, 144.8, 150.1,
151.7, 151.9. MS m/z: 266, 268 (M+). Anal. Calcd for C11H11N4O2Cl: C, 49.54; H, 4.16; N, 21.01. Found:
C, 49.46; H, 4.23; N, 20.92.
[rel-(1R,2R,4R,5S)-4-(6-Amino-9H-purin-9-yl)-6-oxabicyclo[3.1.0]hex-2-yl]methanol (10a):
A mixture of 9b (100 mg) and MeOH (10 mL) saturated with NH3 was heated in a sealed tube at 60 °C
overnight. The mixture was concentrated under reduced pressure, and the residue was separated by flash
chromatography with AcOEt as an eluent to give 40 mg (43%) of 10a.
1
mp 183-184 °C (MeOH). IR (nujol): 3300, 3325 cm-1. H-NMR (MeOH-d4) δ: 1.25 (dt, 1H, J=12.6, 9.7

248
HETEROCYCLES, Vol. 64, 2004
Hz), 2.30 (dt, 1H, J=12.6, 8.0 Hz), 2.45 (dt, 1H, J= 16.0, 8.0 Hz), 3.67 (dd, 1H, J=10.3, 5.7 Hz), 3.72 (dd,
1H, J=10.3, 8.0 Hz), 3.75 (dd, 1H, J=2.9, 1.1 Hz), 3.87 (dd, 1H, J=2.9, 1.1 Hz), 5.10 (t, 1H, J=9.0 Hz),
8.20 (s, 1H), 8.25 (s, 1H). 13C-NMR (MeOH-d4) δ: 28.5, 41.6, 54.9, 56.5, 57.1, 61.5, 118.5, 139.1, 149.3,
152.5, 155.9. MS m/z: 247 (M+). Anal. Calcd for C11H13N5O2: C, 53.43; H, 5.30; N, 28.32. Found:
C,53.38; H, 5.54; N, 28.08.
rel-[(1R,2R,4R,5S)-4-(6-Cyclopropylamino-9H-purin-9-yl)-6-oxabicyclo[3.1.0]hex-2-yl]methanol
(10b):
A mixture of 9b (133 mg, 0.5 mmol), cyclopropylamine (114 mg, 2 mmol) and MeOH (10 mL) in a
sealed tube was heated at 60 °C overnight. The mixture was concentrated under reduced pressure, and the
residue was separated by flash chromatography with AcOEt as an eluent to give 71 mg (50%) of 10b.
1
mp 161-162 °C (MeOH). IR (nujol): 3292 cm-1. H-NMR (MeOH-d4) δ: 0.61-0.65(m, 2H), 0.84-0.92
(m, 2H), 1.24 (dt, 1H, J=12.6, 9.7 Hz), 2.29 (dt, 1H, J=16.0, 7.5 Hz), 2.45 (dt, 1H, J=16.0, 7.5 Hz), 2.95
(br s, 1H), 3.66 (dd, 1H, J=6.0, 10.5 Hz), 3.71 (dd, 1H, J=8.1, 10.5 Hz), 3.74 (d, 1H, J=2.9 Hz), 3.86 (s,
1H), 5.08 (t, 1H, J=8.6 Hz), 8.20 (s, 1H), 8.29 (s, 1H). 13C-NMR (MeOH-d4) δ: 7.5, 24.3, 29.6, 42.6,
55.8, 57.6, 58.2, 62.5, 120.1, 139.8, 149.6, 153.5, 156.8. MS m/z: 287 (M+). Anal. Calcd for C14H17N5O2:
C, 58.52; H, 5.96; N, 24.37. Found: C, 58.69; H, 6.08; N, 24.25.
ACKNOWLEDGEMENTS
The authors thank Kuraray Co., Ltd. for providing the ABH.
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